Selective serotonin reuptake inhibitors (hereinafter called SSRIs), such as racemic citalopram and escitalopram, have become first-choice therapeutics in the treatment of depression primarily due to their superior efficacy compared to tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs). SSRIs function by inhibiting the reuptake of the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) by nerve cells at synapses. As a result, serotonin persists in the synaptic gap and has the chance to stimulate receptors of recipient cells.
There is typically a delay (e.g., 2 weeks) between the initiation of SSRI treatment and an observed therapeutic affect. The neurological bases for the delay is that administration of SSRIs immediately increases synaptic serotonin and stimulates the inhibitory 5-HT1A autoreceptor, turning down spontaneous firing of 5-HT neurons. After continued SSRI administration, the 5-HT1A autoreceptor desensitizes and normal firing of the 5-HT neuron returns.
Escitalopram is the S-enantiomer of citalopram and has the following structure:
Methods of preparing escitalopram are disclosed in, for example, U.S. Pat. Nos. Re. 34,712 and 6,566,540 and International Publication Nos. WO 03/000672, WO 03/006449, WO 03/051861, and WO 2004/083197, all of which are hereby incorporated by reference.
International Publication Nos. WO 01/03694 and WO 02/087566, which are hereby incorporated by reference, disclose the use of escitalopram in the treatment of various mental disorders including major depressive disorder, general anxiety disorder, social anxiety disorder, post traumatic stress disorder, panic attacks, acute stress disorder, eating disorders (such as bulimia, anorexia and obesity), phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder and drug abuse. International Publication No. WO 02/087566 also discloses the use of escitalopram for the treatment of patients who have failed to respond to initial treatment with a conventional SSRI, in particular patients with major depression disorder who have failed to respond to initial treatment with a conventional SSRI.
Escitalopram oxalate is currently marketed in the United States as Lexapro® for the treatment of major depressive disorder and generalized anxiety disorder. Lexapro® is available in 5, 10 and 20 mg escitalopram immediate release tablets (as an oxalate salt) and in a 5 mg/mL oral solution.
A modified release formulation of escitalopram oxalate prepared by melt granulation is disclosed in International Publication No. WO 01/22941. Modified release formulations of SSRIs, such as citalopram hydrobromide and escitalopram oxalate, having particular dissolution profiles are disclosed in International Publication No. WO 2004/058299.
Side effects associated with esitalopram include nausea, insomnia, somnolence, increased sweating, fatigue, and sexual dysfunction (including, but not limited to, ejaculation disorder, anorgasmia, and decreased libido).
Bupropion hydrochloride, which is described in U.S. Pat. Nos. 3,819,706 and 3,885,046, is currently marketed as Wellbutrin®, Wellbutrin SR®, and Wellbutrin XL® for the treatment of major depressive disorder and Zyban® as an aid to smoking cessation treatment. Bupropion is an aminoketone-derivative chemically unrelated to other currently available antidepressants (e.g., selective serotonin-reuptake inhibitors, tricyclics, and tetracyclics). While the neurochemical mechanisms of the antidepressant and smoking cessation effects are unknown, noradrenergic pathways and/or dopaminergic effects appear to be primarily involved. Bupropion does not inhibit monoamine oxidase and is a weak blocker of serotonin and norepinephrine uptake.
Wellbutrin® (an immediate release bupropion hydrochloride formulation) is supplied as 75 and 100 mg tablets which are to be administered three times a day, preferably with at least 6 hours between successive doses. Controlled release formulations of bupropion hydrochloride have been developed.
For example, U.S. Pat. No. Re. 33,994 discloses a controlled release bupropion tablet formulation comprising a bupropion hydrochloride core and a coating comprised of a water-insoluble, water-permeable film forming coating and a particulate, water-soluble, pore-forming material. However, because 25-70% of the bupropion is released within 4 hours and 40-90% within 6 hours, at least twice daily dosing is still typically required.
U.S. Pat. Nos. 5,358,970, 5,763,493, and 5,731,000 disclose bupropion hydrochloride formulations containing a stabilizer to prevent the degradation of the bupropion hydrochloride.
U.S. Pat. No. 5,427,798 discloses a controlled release bupropion tablet formulation containing hydroxypropyl methylcellulose. More than half of the bupropion is preferably released in distilled water in 4 hours. Because of this rapid release rate, the formulation typically is administered multiple times in a day.
U.S. Pat. Nos. 6,096,341 and 6,143,327 disclose a controlled release tablet of bupropion hydrochloride, free of stabilizers and pore-forming agents. The tablet is comprised of a core consisting essentially of bupropion hydrochloride, a binder, and a lubricant, and a coating consisting essentially of a water-insoluble, water-permeable, film-forming polymer, a plasticizer, and a water-soluble polymer.
U.S. Pat. No. 6,905,708 and U.S. Patent Application Publication Nos. 2003/0161874 and 2005/0147678 disclose a once a day bupropion hydrochloride formulation comprising coated pellets of bupropion hydrochloride.
In DeVane, J. Clin. Psychiatry 2003, 64 (suppl. 18):14-19, the results of clinical studies of immediate release and controlled release formulations of antidepressants were compared in relation to nausea leading to drug discontinuation. The author stated that “more stable pharmacokinetic profiles might be the cause for the low occurrence of nausea with some controlled-release newer antidepressants” but a “connection has not been proven.”
According to Gerner et al., Biol. Psychiatry, 1998, 43:101 S, abstract 336 (“Gerner I”), “[b]upropion has been added to SSRIs for treatment of inadequate clinical response, SSRI sexual dysfunction, and for comorbid ADD and depression associated with [p]anic or [o]bsessive [c]ompulsive [d]isorders.” See also Kennedy et al. J. Clin. Psychiatry, 2002, 63: 181-186 (study regarding the pharmacokinetic, therapeutic, and sexual dysfunction effects of combinations of bupropion SR with venlafaxine, paroxetine, or fluoxetine); Gerner et al., Biol. Psychiatry, 1998, 43:99 S, abstract 329 (“Gerner II”); Ashton et al., J. Clin. Psychiatry, 1998, 59(3):112-115 (study regarding the use of bupropion as an antidote for serotonin reuptake inhibitor (paroxetine, fluoxetine, sertraline, venlafaxine, or fluvoxamine) induced sexual dysfunction); Gitlin et al., J. Sex & Marital Therapy 2002, 28:131-138 (study regarding a bupropion sustained release formulation as a treatment for SSRI-induced sexual side effects). However, treatment of SSRI-induced sexual dysfunction with bupropion has not been proven to be effective. According to Sturpe et al., J. Family Practice August 2002, 51(8):1681, a double-blind placebo-controlled trial comparing augmentation therapy with bupropion showed equal improvement in sexual function to placebo. Furthermore, bupropion has increased seizure incidence compared with other antidepressants. Gerner II, supra (reporting on 3 cases of major motor seizures in previously seizure-free depressed patients after combining bupropion with fluoxetine or fluvoxamine); see also Gerner I, supra.
Studies suggest that between 29% and 46% of depressed patients fail to respond fully with antidepressant treatment of adequate dose and duration. Fava et al., Psychiatr. Clin. North Am., 1996, 19(2):179-200; Fava et al., Ann. Clin. Psychiatry, 2003, 15(1): 17-22. Lam et al., J. Clin. Psychiatry, 2004, 65:337-340, reported the results of a clinical study comparing combining citalopram and bupropion SR versus switching to a monotherapy in patients with treatment-resistant depression. According to the authors, “[t]he results of this cohort study suggest that combining citalopram and bupropion SR is more effective than switching to a monotherapy.”
U.S. Pat. No. 6,342,496 discloses bupropion metabolites for treating disorders ameliorated by inhibition of neuronal monoamine reuptake. The bupropion metabolite can be adjunctively administered with an additional pharmacologically active compound, such as an SSRI, 5-HT3 inhibitor, or nicotine.
There is a need for methods of treating central nervous system disorders with fewer side effects than prior methods and which are effective in treatment-resistant patients.
There is also a need for methods of SSRI treatment that do not exhibit an initial reduction in 5-HT neuron activity and which do not exhibit a delay in SSRI therapeutic effect.